CLINUVEL today announced a novel clinical program evaluating
afamelanotide as a treatment in early-stage Parkinson’s Disease (PD
or Parkinson’s) in fair-skinned patients. The program objectives
are to determine whether afamelanotide – through melanocortin-1
receptor (MC1R) activation – is able to lower α-synuclein (a toxin)
in blood levels in PD patients, and positively affect neurons of
the midbrain. MC1R is known to be a key receptor in brain and skin
cells.
In large studies, it was found that fair-skinned
patients have a higher risk of PD associated with a malfunctioning
MC1R.a, 1-2 Since afamelanotide is known to optimise the function
of the MC1R, it is hypothesised that the drug treatment would have
a positive effect in PD by lowering α-synuclein, as recently
demonstrated in preclinical studies.²ˉ³ Afamelanotide is marketed
in Europe and the USA as SCENESSE® for patients diagnosed with
erythropoietic protoporphyria (EPP).
Evidence for use of afamelanotide in
Parkinson’s Disease
Worldwide, individuals born with red hair and
fair skin are found to have a loss of function of MC1Rs – expressed
on skin and brain cells – and to carry an increased risk of
Parkinson’s and melanoma.⁴¯⁵
In various Parkinson’s models it has been
illustrated that an MC1R-binding drug – such as afamelanotide –
enables cellular protection against α-synuclein, a toxic substance
found in the neurons of PD patients. In preclinical models, the use
of afamelanotide has been shown to improve neurodegenerative
conditions.⁶
Following decades of human use, it has been well
established that afamelanotide strongly binds to MC1R and optimises
cellular functions (signalling) through pharmacological
activation.
The CUV901 study is the first human study
evaluating the effect of afamelanotide in PD as a therapeutic
option.
Study design – CUV901
The Phase IIa CUV901 study will evaluate six
fair-skinned patients with early symptoms of PD who are not yet
receiving medicinal therapy.
The first objectives of the open-label study are
to focus on the safety of afamelanotide, while determining
α-synuclein in blood, and assessing visual changes in the midbrain.
Secondary endpoints are to assess cognitive functions. The study
design has obtained ethics and regulatory approval.b
Patients between 40 and 85 years old will
receive 11 doses of 0.08 mg per kilogram body weight of
afamelanotide on each day of drug administration, over a study
duration of 56 days. The first patients are expected to enrol
before the end of 2024.
Commentary
“We are immensely pleased to initiate a highly
innovative study for afamelanotide,” CLINUVEL’s Chief Scientific
Officer, Dr Dennis Wright said. “It marks a real breakthrough to
conduct this study in Parkinson’s after lengthy regulatory
discussions and preparation.
“At the heart of the problem in Parkinson’s lies
the loss of dopamine producing neurons in the brain due to toxicity
caused by α-synuclein. There is now evidence that afamelanotide –
by binding to MC1R – could maintain stability and integrity of the
affected neurons and slow down progression of the disorder.
“By analysing blood and brain scans of the
substantia nigra, we will learn of afamelanotide’s potential effect
in Parkinson’s. The ability to do something for this group of
patients results from decades of clinical research and a focus on
translating inhouse knowledge,” Dr Wright concluded.
About Parkinson’s Disease
Parkinson’s Disease is a progressive and
degenerative disorder caused by oxidative stress and
neuroinflammation. Symptoms consist of progressive loss of motor
functions and increased tremor, as well as dementia, depression,
sleep disorders and a range of autonomic dysfunctions. Ultimately
PD can result in adverse clinical outcomes, contributing to over
200,000 deaths annually.
PD is characterised by the loss of dopamine
producing neurons predominantly in the substantia nigra (SN) of the
brain, while a high accumulation is seen of the neurotoxin
α-synuclein.
It is thought that treatment of patients with
early symptoms provides a better prognosis.
The current standard of care in PD is levodopa,
monoamine oxidase B (MAO-B) inhibitors or dopamine agonists, which
all aim to provide symptomatic relief but are not able to slow
neurodegeneration. These medications become less effective as the
disease progresses and escalating doses may be required.
Notes
a Epidemiological analyses from 120,000 US
individuals revealed that fair skinned Parkinson’s patients have an
increased risk of developing melanoma in a lifetime, both
populations carrying a defective MC1R function.1 Afamelanotide is
known to possess very high binding property (agonist) to MC1R and
offer cellular protection by overcoming a loss-of-function of the
receptor in patients with fair skin with red hair phenotype.b
Alpha-synuclein (α-synuclein) – as a measure of disease progress -
is used as a biomarker in blood samples of PD patients.
References
-
Gao, X., et al. (2009). Genetic determinants of hair color and
Parkinson’s disease risk. Ann Neurol. 65:76–82.
-
Chen, X., et al. (2017). The Melanoma-Linked “Redhead” MC1R
Influences Dopaminergic Neuron Survival. Annals of Neurology,
81(3), 395–406.
-
Chen, X., et al. (2017). Red hair, MC1R variants, and risk for
Parkinson’s disease – a meta‐analysis. Annals of Clinical and
Translational Neurology, 4(3), 212–216.
-
Gao, X., et al. (2009). Family history of melanoma and Parkinson
disease risk. Neurology 73:1286–1291.
-
Kareus, S.A., et al. (2012). Shared Predispositions of Parkinsonism
and Cancer: a Population-Based Pedigree-Linked Study. Arch Neurol.
69:1572–1577.
-
Cai, W., et al. (2022). Melanocortin 1 receptor activation protects
against alpha-synuclein pathologies in models of Parkinson’s
disease. Molecular Neurodegeneration, 17(1), 16.Srivast, P., et al.
(2023). Peripheral MC1R activation modulates immune responses and
is neuroprotective in a mouse model of Parkinson’s disease.
Research Square, rs.3.rs-3042571.
About CLINUVEL PHARMACEUTICALS LIMITED
CLINUVEL (ASX: CUV; ADR LEVEL 1: CLVLY; Börse
Frankfurt: UR9) is a global specialty pharmaceutical group focused
on developing and commercialising treatments for patients with
genetic, metabolic, systemic, and life-threatening, acute
disorders, as well as healthcare solutions for specialised
populations. As pioneers in photomedicine and the family of
melanocortin peptides, CLINUVEL’s research and development has led
to innovative treatments for patient populations with a clinical
need for systemic photoprotection, assisted DNA repair,
repigmentation and acute or life-threatening conditions who lack
alternatives. CLINUVEL’s lead therapy, SCENESSE® (afamelanotide
16mg), is approved for commercial distribution in Europe, the USA,
Israel, and Australia as the world’s first systemic photoprotective
drug for the prevention of phototoxicity (anaphylactoid reactions
and burns) in adult patients with erythropoietic protoporphyria
(EPP). Headquartered in Melbourne, Australia, CLINUVEL has
operations in Europe, Singapore, and the USA. For more information,
please go to https://www.clinuvel.com.
Authorised for ASX release by the Board of Directors of
CLINUVEL PHARMACEUTICALS LTD.
Head of Investor Relations
Mr Malcolm Bull, CLINUVEL PHARMACEUTICALS
LTD
Investor Enquiries
https://www.clinuvel.com/investors/contact-us
Forward-Looking Statements
This release contains forward-looking
statements, which reflect the current beliefs and expectations of
CLINUVEL’s management. Please see the full statement at
https://www.clinuvel.com/2024/06/afamelanotide-in-fair-skinned-parkinsons-patients-20240618/.
Contact:
Tel: +61 3 9660 4900 Fax: +61 3 9660
4909Email: mail@clinuvel.comAustralia (Head
Office), Level 22, 535 Bourke Street, Melbourne, Victoria,
3000, Australia
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